RESUMEN

Parenteral depot systems can provide a constant release of drugs over a few days to months. Most of the parenteral depot products on the market are based on poly(lactic acid) and poly(lactide-co-glycolide) (PLGA). Studies have shown that acidic monomers of these polymers can lead to nonlinear release profiles or even drug inactivation before release. Therefore, finding alternatives for these polymers is of great importance. Our previous study showed the potential of starch as a natural and biodegradable polymer to form a controlled release system. Subarachnoid hemorrhage (SAH) is a life-threatening type of stroke and a major cause of death and disability in patients. Nimotop® (nimodipine (NMD)) is an FDA-approved drug for treating SAH-induced vasospasms. In addition, NMD has, in contrast to other Ca antagonists, unique neuroprotective effects. The oral administration of NMD is linked to variable absorption and systemic side effects. Therefore, the development of a local parenteral depot formulation is desirable. To avoid the formation of an acidic microenvironment and autocatalytic polymer degradation, we avoided PLGA as a matrix and investigated starch as an alternative. Implants with drug loads of 20 and 40% NMD were prepared by hot melt extrusion (HME) and sterilized with an electron beam. The effects of HME and electron beam on NMD and starch were evaluated with NMR, IR, and Raman spectroscopy. The release profile of NMD from the systems was assessed by high-performance liquid chromatography. Different spectroscopy methods confirmed the stability of NMD during the sterilization process. The homogeneity of the produced system was proven by Raman spectroscopy and scanning electron microscopy images. In vitro release studies demonstrated the sustained release of NMD over more than 3 months from both NMD systems. In summary, homogeneous nimodipine-starch implants were produced and characterized, which can be used for therapeutic purposes in the brain.

Asunto(s)

Nimodipina , Parasimpatolíticos , Humanos , Nimodipina/química , Preparaciones de Acción Retardada , Almidón , Portadores de Fármacos/química , Polímeros/química , Encéfalo

RESUMEN

Currently, reducing particle size or preparing drugs into amorphous forms are widely used methods to improve the solubility and dissolution rate of insoluble drugs. The purpose of this study was to prepare nimodipine amorphous nanopowder (NMD-NAP) using nimodipine (NMD) as a model drug to increase the solubility and dissolution rate of insoluble drugs by the combined effect of reducing the particle size and preparing the drug into an amorphous form. The NMD-NAP was successfully prepared by quenching cooling combined with wet milling and spray drying. The prepared NMD-NAP was shown to have good redispersibility by particle size analysis. The shapeof NMD-NAP was characterized by SEM and AFM, showing a spherical or spheroidal structure. The results of PLM, DSC, XRD, and FT-IR indicated that the drug existed in an amorphous form. The dissolution study showed that the dissolution rate of NMD in NMD-NAP was improved about 5 times that of pure NMD and 3 times that of nimodipine nanocrystalline (NMD-NC), indicating the combination of nano size and amorphous form produced a synergistic effect that could significantly increase the dissolution rate of NMD. Due to the significantly improved solubility and good industrial feasibility of the prepared NMD-NAP, the preparation of insoluble drugs into amorphous nanopowders is an effective method to improve the solubility of insoluble drugs and has good application prospects.

Asunto(s)

Nimodipina , Secado por Pulverización , Nimodipina/química , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X , Solubilidad , Tamaño de la Partícula

RESUMEN

The aim of the present study was to manufacture new orally disintegrating tablets containing nimodipine-hydroxypropyl-ß-cyclodextrin and nimodipine-methyl-ß-cyclodextrin inclusion complexes. For obtaining a better quality of the manufactured tablets, three methods of the preparation of inclusion complexes, in a 1:1 molar ratio, were used comparatively; namely, a solid-state kneading method and two liquid state coprecipitation and lyophilization techniques. The physical and chemical properties of the obtained inclusion complexes, as well as their physical mixtures, were investigated using Fourier transformed infrared spectroscopy, scanning electron microscopy, X-ray diffraction analyses, and differential scanning calorimetry. The results showed that the lyophilization method can be successfully used for a better complexation. Finally, the formulation and precompression studies for tablets for oral dispersion, containing Nim-HP-ß-CD and Nim-Me-ß-CD inclusion complexes, were successfully assessed.

Asunto(s)

Química Farmacéutica , Nimodipina , 2-Hidroxipropil-beta-Ciclodextrina , Química Farmacéutica/métodos , Nimodipina/química , Solubilidad , Comprimidos , beta-Ciclodextrinas

RESUMEN

A new series of nonionic gemini amphiphiles have been synthesized in a multi-step chemoenzymatic approach by using a novel A2 B2 -type central core consisting of conjugating glycerol and propargyl bromide on 5-hydroxy isophthalic acid. A pair of hydrophilic monomethoxy poly(ethylene glycol) (mPEG) and hydrophobic linear alkyl chains (C12 /C15 ) were then added to the core to obtain amphiphilic architectures. The aggregation tendency in aqueous media was studied by dynamic light scattering, fluorescence spectroscopy and cryogenic transmission electron microscopy. The nanotransport potential of the amphiphiles was studied for model hydrophobic guests, that is, the dye Nile Red and the drug Nimodipine by using UV/Vis and fluorescence spectroscopy. Evaluation of the viability of amphiphile-treated A549 cells showed them to be well tolerated up to the concentrations studied. Being ester based, these amphiphiles exhibit stimuli-responsive sensitivity towards esterases, and a rupture of amphiphilic architecture was observed in the presence of immobilized Candida antarctica lipase (Novozym 435), thus facilitating release of the encapsulated guest from the aggregate.

Asunto(s)

Portadores de Fármacos/química , Células A549 , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/farmacología , Proteínas Fúngicas/metabolismo , Humanos , Hidrólisis , Interacciones Hidrofóbicas e Hidrofílicas , Lipasa/metabolismo , Microscopía Confocal , Microscopía Electrónica de Transmisión , Nanoestructuras/química , Nimodipina/química , Nimodipina/metabolismo , Oxazinas/química , Polietilenglicoles/química

RESUMEN

Nimodipine is a dihydropyridine calcium channel blocker that exhibits higher selectivity toward cerebral blood vessels compared with other members of the same class. It has been shown to improve outcomes and prevent delayed cerebral ischemia in the setting of aneurysmal subarachnoid hemorrhage, a life-threatening brain bleed. Nimodipine is a chiral compound and it is marketed as a racemic mixture of (+)-R and (-)-S enantiomers. (-)-S-Nimodipine is approximately twice as potent a vasorelaxant as the racemic mixture and is more rapidly eliminated than the (+)-R counterpart following oral dosing. Few analytical procedures have been reported to determine nimodipine enantiomers in biological samples; however, the reported methods were time-consuming, involved multistep extraction procedures and required large sample volumes. Herein, we present an LC-MS/MS method for quantifying nimodipine enantiomers in human plasma using a small sample volume (0.3 ml) and a single liquid-liquid extraction step. The peak area ratios were linear over the tested concentration ranges (1.5-75 ng/ml) with r2 > 0.99. The intraday CV and percentage error were within ±14% while the interday values were within ±13%, making this analytical method feasible for research purposes and pharmacokinetic studies.

Asunto(s)

Cromatografía Liquida/métodos , Nimodipina/sangre , Nimodipina/química , Espectrometría de Masas en Tándem/métodos , Humanos , Modelos Lineales , Nimodipina/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estereoisomerismo , Hemorragia Subaracnoidea/tratamiento farmacológico , Vasodilatadores/sangre , Vasodilatadores/química , Vasodilatadores/farmacocinética

RESUMEN

Nimodipine is a 1,4-Dihydropyridine type calcium antagonist routinely used to control blood pressure and reduce the risk of secondary ischemia after aneurismal subarachnoid hemorrhage. Additionally, Nimodipine has unique neuroprotective properties. With respect to brain related applications, the full potential of the desired local effect can often not be realized after systemic administration due to systemic side effects. Therefore, it was our aim to develop a biodegradable drug delivery system for the local controlled release of the drug inside the brain. As a suitable and biodegradable system we successfully electrospun PLGA fibers containing 1 and 10% drug. The results of DSC and X-Ray diffractometry measurements indicate that Nimodipine was incorporated in the polymer matrix in the amorphous state. No drug recrystallization was detected for up to 6 months. Electron-beam sterilization was tried but reduced the drug content of the fiber mats considerably. A sustained drug release over 4-8 days was observed, highly depended on release conditions. The Nimodipine fiber mats exhibited no cell toxicity. In contrast, the electrospun fibers were able to significantly reduce cell death in in vitro cell models of oxidative, osmotic and heat-induced cell stress in Schwann cells, neuronal cells as well as immortalized and primary astrocytes. Therefore, electrospun Nimodipine loaded PLGA fibers represent a promising drug delivery system to realize the druǵs benefits for its intracranial use.

Asunto(s)

Regeneración Nerviosa/efectos de los fármacos , Nimodipina/química , Nimodipina/farmacología , Animales , Astrocitos/efectos de los fármacos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Sistemas de Liberación de Medicamentos/métodos , Ratones , Neuronas/efectos de los fármacos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ratas , Ratas Wistar , Células de Schwann/efectos de los fármacos

RESUMEN

Single-atom catalysts (SACs) often exhibit superior activity and selectivity in heterogeneous catalysis because of their maximized atom utilization and unique coordination environments. However, most reported studies about SACs in heterogeneous catalysis focus on model reactions with simple molecules. In addition, many reported single atoms are confined in microporous structures, hindering the mass transfer of molecules with large sizes, thus limiting their practical applications in industry. In this study, we report a molten salt-assisted method to synthesize metal single atoms anchored on a hierarchical porous nitrogen-doped carbon support (denoted as M1/h-NC, M includes Co, Fe, Ni, Mn, and Cu). Taking Co1/h-NC as an example, compared to the control sample which has Co single atoms being encapsulated in a microporous N-doped carbon support (denoted as Co1/m-NC), Co1/h-NC exhibits significantly higher catalytic activity in the selective hydrogenation of large-sized pharmaceutical molecules, such as nimodipine (calcium channel blocker) and 2-(3',4'-methylenedioxyphenylethyl)quinoline (antispasmodic natural alkaloid intermediate). The superior catalytic performance of Co1/h-NC is directly ascribed to the integration of the advantages of single-atom active sites and hierarchical mesoporous structure, which is beneficial for the mass transfer of molecules with large sizes and enables nearly all the Co single atoms to be accessible for catalytic reactions.

Asunto(s)

Carbono/química , Metales/química , Nitrógeno/química , Alcaloides/química , Benzaldehídos/química , Catálisis , Industria Farmacéutica , Hidrogenación , Nimodipina/química , Porosidad

RESUMEN

We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca2+ channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs 3a-t, resulting from the juxtaposition of nimodipine, a Ca2+ channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6-dimethyl-4-[4-(prop-2-yn-1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (3a), as an attractive antioxidant (1.75 TE), Ca2+ channel antagonist (46.95% at 10 µM), showing significant neuroprotection (38%) against H2O2 at 10 µM, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.

Asunto(s)

Antioxidantes/química , Antioxidantes/fisiología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Calcio/metabolismo , Línea Celular Tumoral , Dihidropiridinas/química , Dihidropiridinas/farmacología , Humanos , Ligandos , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Neuroprotección/efectos de los fármacos , Nimodipina/química , Nimodipina/farmacología

RESUMEN

BACKGROUND: Nimodipine is a calcium channel blocker frequently used in critical care settings. It is mainly absorbed in the upper gastrointestinal tract. Accordingly, the development of gastroretentive formulation will be beneficial. The benefit would be maximized for critical care patients if the developed system was in liquid form to facilitate the administration through nasogastric tubing. OBJECTIVE: Development of gastro-retentive liquid oral controlled release formulation of nimodipine through in situ gellation. METHODS: Nimodipine dissolution was improved by solid dispersion (SD) using poloxamer 407. Sodium alginate solutions (1, 1.5 and 2%w/v) were loaded with the optimized SD microparticles. Carboxymethylcellulose was added to modulate the release and to augment mucoadhesion power. All in situ gelling alginate solutions were characterized regarding viscosity, gelling capacity and drug release. SD microparticles showed considerable improvement in nimodipine dissolution. RESULTS: All alginate systems were pourable. Increasing alginate concentration increased the gelling capacity and reduced drug release rate. The addition of carboxymethylcellulose produced greater control over drug release rate. X-ray radiography showed successful stomach-retention over 8 hours in rabbits, which correlates with the controlled release pattern of the developed systems. CONCLUSION: The study provides the formulator with a range of gastroretentive controlled release formulations of nimodipine while maintaining the convenience of administration through nasogastric tubing with the potential for enhanced bioavailability.

Asunto(s)

Bloqueadores de los Canales de Calcio/administración & dosificación , Sistemas de Liberación de Medicamentos , Nimodipina/administración & dosificación , Adhesividad , Administración Oral , Alginatos/administración & dosificación , Alginatos/química , Animales , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Carboximetilcelulosa de Sodio/administración & dosificación , Carboximetilcelulosa de Sodio/química , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos , Mucosa Gástrica/metabolismo , Masculino , Nimodipina/química , Nimodipina/farmacocinética , Poloxámero/administración & dosificación , Poloxámero/química , Conejos

RESUMEN

The purpose of this work was to develop a robust hot-melt extrusion and strand pelletization process for manufacturing pellets with an immediate release (IR) of a poorly water-soluble active pharmaceutical ingredient (API), nimodipine. The robustness of pharmaceutical continuous manufacturing processes and of its control strategy is vital for competitiveness to traditional batch-manufacturing. Therefore, first the sensitivity of product quality, process stability, and process monitoring tools to i) parameter changes due to control actions and ii) typical process deviations, i.e., feeding errors, was investigated in a design of experiments (DoE). Thereby, die melt pressure was found to be highly sensitive to composition deviations, i.e. a limiting factor for process stability. Especially critical were deviations to increased HPMC content, since it behaved as a filler in the melt. Pelletization, or pellet size and size distribution respectively, were found to be sensitive to an increased throughput, due to the resulting insufficient strand cooling before the pelletizer. API dissolution in contrast, was found to be robust across the entire investigated range of formulation and process settings. Second, a design space for the production of IR pellets for subsequent tableting was established, and finally, a technical control strategy was developed to ensure a robust process. Near-infrared (NIR) spectroscopy was applied to monitor API content and the sensitivity of the residence time distribution (RTD) was investigated by means of tracer measurements. NIR-based API content monitoring and RTD models for material tracking were found to be at risk after processing melt with high HPMC content, due to a lack of purging by less viscous formulation compositions.

Asunto(s)

Composición de Medicamentos/métodos , Liberación de Fármacos , Tecnología de Extrusión de Fusión en Caliente , Derivados de la Hipromelosa/química , Metilmetacrilatos/química , Nimodipina/química

RESUMEN

PURPOSE: Nimodipine (NMP) is a clinical dihydropyridine calcium antagonist. However, the clinical application of NMP is limited by poor water solubility and low oral bioavailability. To overcome these drawbacks, this study designed optimal NMP-incorporated nanostructured lipid carriers (NLCs). METHODS: High-pressure homogenization was successfully applied to prepare NMP-NLC, and the nanoparticle morphology was observed by a transmission electron microscope. The existence form of NMP in NMP-NLC was investigated by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy, respectively. The in vitro release study was performed by the dialysis method, and in vivo studies including in situ intestinal perfusion and pharmacokinetics were investigated in rats with NMP detected by high-performance liquid chromatography. RESULTS: The obtained NMP-NLC shared a spherical shape of ~70 nm with a smooth surface and high encapsulation efficiency of 86.8%±2.1%. Spectroscopy indicated that the drug was in an amorphous state. The NMP-NLC exhibited a sustained release and diverse release profiles under different release medium, which mimicked the physiological environment. Moreover, an in situ intestinal perfusion experiment revealed that NMP-NLC could be mainly absorbed by the small intestine. Remarkable improvements in Cmax and AUC0-∞ from NMP-NLC were obtained from pharmacokinetic experiments, and the relative bioavailability of NMP-loaded nanostructured lipid systems was 160.96% relative to NMP suspensions. CONCLUSION: Collectively, the NLCs significantly enhanced the oral bioavailability of NMP and might provide a promising nanoplatform for hydrophobic drug delivery.

Asunto(s)

Lípidos/química , Nanoestructuras/química , Nimodipina/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Masculino , Nanoestructuras/ultraestructura , Nimodipina/sangre , Nimodipina/química , Nimodipina/farmacocinética , Tamaño de la Partícula , Ratas Sprague-Dawley , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Difracción de Rayos X

RESUMEN

The objective of the current study was to optimize for the first time the formulation variables of self-emulsified drug delivery system (SEDDS) based on drug solubilization during lipolysis under a biorelevant condition of digestion such as lipase activity, temperature, pH, fed-fasting state, etc. Nimodipine (ND), a BCS class II, was used as a model drug to prepare the SEDDS. Various oils, surfactants, and cosurfactants were screened for their solubilization potential of ND. Area of self-emulsification was identified using various ternary phase diagrams. Box-Behnken design was employed to investigate effects of formulation variables on various dispersion, emulsification, and lipolysis characteristics of SEDDS. Among 26 candidate formulations, highest ND solubility of 12.72%, 11.09% and 11.2% w/w were obtained in peppermint oil as the oily phase, Cremphor EL as the surfactant and PEG400 as the cosurfactant, respectively. Cremphor EL was the most significant factor to decrease SEDDS droplet size to 30.16 nm. On the other hand, increasing the oil concentration was found to significantly increase the polydispersity index up to 0.31. A faster emulsification rate of 3.37%/min was obtained at higher Cremphor El/PEG 400 ratio. Increasing the percentage of lipid components of SEDDS resulted in lower rate of lipolysis with less recovery of ND in aqueous phase. Under fed state, percentage of lipolysis of optimized formulation was less than that observed under fasted state. However, lowest rate and percentage of lipolysis were observed in lipolysis media without phospholipids and bile salts. Hence, this study demonstrated that in vitro lipolysis could be used as a surrogate approach to distinguish effects of formulation variables on fate of SEDDS upon digestion. Further studies are in progress to identify the lipolytic products of the employed excipients by LC-MS/MS.

Asunto(s)

Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos , Lipólisis/efectos de los fármacos , Nimodipina/administración & dosificación , Administración Oral , Animales , Emulsiones , Excipientes/química , Lípidos/química , Nimodipina/química , Aceites/química , Tamaño de la Partícula , Solubilidad , Tensoactivos/química , Porcinos

RESUMEN

This work evaluates several compositions of an amorphous solid dispersion (ASD) comprising nimodipine (NMD) as poorly soluble model API in a dual-polymer carrier system. HPMC E5 and Eudragit E were used for the two polymeric carriers. The formulation was designed for hot-melt extrusion (HME) and subsequent strand pelletization. The aim was to identify a formulation window with desired functional ASD performance, i.e. physical stability and immediate API release, as well as processability in strand pelletization. Samples were prepared using small-scale methods, such as vacuum compression molding (VCM) and benchtop extrusion. Miscibility and phase studies were performed for a wide range of polymer ratios and three levels of API content (10-30% w/w). Ternary ASD formulations were phase-separated, yet physically stable upon exposure to elevated temperature/humidity. A study of phase composition showed that the drug molecules were predominantly solubilized in the Eudragit E fraction of the formulation. The miscibility study and Fourier-transform infrared spectroscopy indicated hydrogen (H)bond interactions between NMD and Eudragit E. In HPMC, the amorphous API was dispersed in polymeric matrix and stabilized due to anti-plasticization and the disruption of intermolecular Hbonding between API molecules. Concerning processability in strand pelletization the formulation is limited at high Eudragit E content. NMD and EE-rich phases exhibit low mixture glass transition, low melt stability and brittle breaking behavior upon strand cutting. The high viscosity and yield point of HPMC contributes to the mechanical robustness of the strand at temperatures relevant for processing. Formulation-intrinsic dissolution rates in VCM ASDs developed as an irregular function of polymer ratio, associated with diverse and competitive dissolution mechanisms in the polymers. With regard to the binary system of NMD with HPMC E5, surface crystallization was observed in VCM ASDs. For extruded pellets this was not the case, and a steady trend of formulation-intrinsic dissolution rate across different polymer ratios was observed. These discrepancies indicated a major influence of shear stress during sample preparation on HPMC-based ASD performance. Finally, a feasible formulation window within a polymer ratio of 1:2-2:3 Eudragit E:HPMC was identified in which Eudragit E acts as a dissolution rate enhancer and ASD stabilizer during dissolution.

Asunto(s)

Química Farmacéutica/métodos , Portadores de Fármacos/química , Nimodipina/administración & dosificación , Polímeros/química , Cristalización , Composición de Medicamentos/métodos , Liberación de Fármacos , Estabilidad de Medicamentos , Excipientes/química , Calor , Humedad , Enlace de Hidrógeno , Derivados de la Hipromelosa/química , Nimodipina/química , Ácidos Polimetacrílicos/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura

RESUMEN

Blood-brain barrier (BBB) was the major obstacle for efficient delivery of therapeutic agents to brain tissue. To overcome this barrier, a novel lactoferrin modified long circulation nanostructured lipid carriers (Lf-NLC) was designed and synthesized for the efficient delivery of neuroprotective agent nimodipine (NMD) to brain tissue. NMD loaded Lf-NLC was optimized to exhibit a small and uniform particle size distribution and high loading content. More interestingly, Lf-NLC showed the excellent neuroprotective effect due to the efficient intracellular delivery NMD, in PC12 based stroke cell model induced by sodium nitroprusside (SNP). Cellular uptake assay indicated that Lf-NLC could be internalized into cytoplasm via Lf-receptor mediated endocytosis pathway. In vivo biodistribution assay demonstrated Lf-NLC could efficiently deliver therapeutic agent to brain tissue, indicating its promising application in brain delivery.

Asunto(s)

Encéfalo/metabolismo , Lactoferrina/química , Nanoestructuras/química , Nimodipina/química , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Nitroprusiato/farmacología , Células PC12 , Ratas

RESUMEN

Nimodipine (NIM) is a calcium channel-blocking agent, which in the solid state exhibits two crystalline modifications, Mode I and Mode II. The first one is a racemic mixture, while the second is a conglomerate. Because the drug has poor aqueous solubility and Mode I is twice as soluble as Mode II, the former is widely preferred for the development of pharmaceutical forms. In order to study the effect of thermal stimuli on the behavior of NIM, an analytical method was developed coupling ATR-FTIR spectroscopy to Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS). The method allowed to monitor the transformations of each polymorph, their respective mixtures and commercial samples, during the thermal treatment. It was observed that Mode II experienced changes during the experiments and the chemometric technique provided the abundance profile and the pure spectra of the different species involved. In this way, it was established that Mode II has two transitions, at 116.8 °C and 131.9 °C, which reflect that Mode II is first transformed into Mode I, which then melts. The liquid phase solidifies to give an amorphous (AM) vitreous solid, which does not revert to the crystalline state. The analysis of a commercial sample of NIM exhibited the similar transformations than Mode II; however, a pronounced decrease was noted in the first transition temperature (95 °C), whereas the second remained essentially unchanged (131.6 °C). This could be a result of the presence of mixtures of Mode I and Mode II (0.32:0.68) in the bulk solid, as confirmed by the analysis of a physical mixture of crystals of Modes I and II. Therefore, it was concluded that the developed ATR-FTIR/MCR-ALS method is suitable for the detailed analysis of the crystalline forms of NIM in bulk drug and enables de study of their possible thermally promoted interconversions.

Asunto(s)

Bloqueadores de los Canales de Calcio/química , Composición de Medicamentos/normas , Nimodipina/química , Química Farmacéutica , Cristalización , Almacenaje de Medicamentos , Análisis de los Mínimos Cuadrados , Control de Calidad , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier/instrumentación , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Temperatura de Transición , Agua

RESUMEN

The pH-responsive intelligent drug release facility of hydrophobically modified chitosan nanoparticles (Chit NPs) (d = 5.2 ±â€¯1.1 nm) was presented in the case of poorly water soluble Ca2+ channel blocker nimodipine (NIMO) drug molecules. The adequate pH-sensitivity, i.e. the suitable drug carrier properties of the initial hydrophilic Chit were achieved by reductive amination of Chit with hexanal (C6-) and dodecanal (C12-) aldehydes. The successful modifications of the macromolecule were evidenced via FTIR measurements: the band appearing at 1412 cm-1 (CN stretching in aliphatic amines) in the cases of the hydrophobically modified Chit samples shows that the CN bond successfully formed between the Chit and the aldehydes. Hydrophobization of the polymer unambiguously led to lower water contents with lower intermolecular interactions in the prepared hydrogel matrix: the initial hydrophilic Chit has the highest water content (78.6 wt%) and the increasing hydrophobicity of the polymer resulted in decreasing water content (C6-chit.: 74.2 wt% and C12-chit.: 47.1 wt%). Furthermore, it was established that the length of the side chain of the aldehyde influences the pH-dependent solubility properties of the Chit. Transparent homogenous polymer solution was obtained at lower pH, while at higher pH the formation of polymer (nano)particles was determined and the corresponding cut-off pH values showed decreasing tendency with increasing hydrophobic feature (pH = 7.47, 6.73 and 2.49 for initial Chit, C6-chit and C12-chit, respectively). Next the poorly water soluble NIMO drug was encapsulated with the C6-chit with adequate pH-sensitive properties. The polymer-stabilized NIMO particles with 10 wt% NIMO content resulted in stable dispersion in aqueous phase, the formation of polymer shell increased in the water solubility/dispersibility of the initial hydrophobic drug. According to the drug release experiments, we clearly confirmed that the encapsulated low crystallinity NIMO drug remained closed in the polymer NPs at normal tissue pH (pH = 7.4, PBS buffer, physiological condition) but at pH < 6.5 which is typical for seriously ischemic brain tissue, 93.6% of the available 0.14 mg/ml NIMO was released into the buffer solution under 8 h release time. According to this in vitro study, the presented pH-sensitive drug carrier system could be useful to selectively target ischemic brain regions characterized by acidosis, to achieve neuroprotection at tissue zones at risk of injury, without any undesirable side effects caused by systemic drug administration.

Asunto(s)

Bloqueadores de los Canales de Calcio/administración & dosificación , Quitosano/química , Portadores de Fármacos/química , Nanopartículas/química , Nimodipina/administración & dosificación , Acidosis , Bloqueadores de los Canales de Calcio/química , Liberación de Fármacos , Humanos , Nimodipina/química

RESUMEN

Currently, a research hotspot in amorphous active pharmaceutical ingredients (APIs) is to understand the key factors that dominate recrystallization and to develop effective methods for stabilizing amorphous forms. Consequently, we investigated the influence of the global molecular mobility and structural properties on the crystallization tendency of three 1,4-dihydropyridine derivatives (nifedipine, nisoldipine, and nimodipine) in their supercooled states using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) techniques. The BDS is also employed to monitor the isothermal crystallization kinetics of supercooled nifedipine and nimodipine at T = 333 K under ambient pressure. As a result, we found that nimodipine exhibits much slower crystallization in comparison to nifedipine. However, nimodipine crystallizes much faster when as little as 10 MPa of pressure is exerted on sample. Such compression-induced crystallization of nimodipine as well as the inherent instability of nifedipine can be solved effectively by preparing coamorphous nifedipine/nimodipine combinations. Interestingly, the high physical stability of nifedipine/nimodipine mixtures is achieved despite the fact that the nimodipine acts as a plasticizer.

Asunto(s)

Composición de Medicamentos/métodos , Nifedipino/química , Nimodipina/química , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Cristalización , Espectroscopía Dieléctrica , Estabilidad de Medicamentos , Simulación de Dinámica Molecular

RESUMEN

Amorphous solid dispersion (ASD) is one of the most versatile supersaturating drug delivery systems to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. PVP based ASD formulation of nimodipine (NMD) has been marketed and effectively used in clinic for nearly 30 years, yet the mechanism by which PVP maintains the supersaturation and subsequently improves the bioavailability of NMD was rarely investigated. In this research, we first studied the molecular interactions between NMD and PVP by solution NMR, using CDCl3 as the solvent, and the drug-polymer Flory-Huggins interaction parameter. No strong specific interaction between PVP and NMD was detected in the nonaqueous state. However, we observed that aqueous supersaturation of NMD could be significantly maintained by PVP, presumably due to the hydrophobic interactions between the hydrophobic moieties of PVP and NMD in aqueous medium. This hypothesis was supported by dynamic light scattering (DLS) and supersaturation experiments in the presence of different surfactants. DLS revealed the formation of NMD/PVP aggregates when NMD was supersaturated, suggesting the formation of hydrophobic interactions between the drug and polymer. The addition of surfactants, sodium lauryl sulfate (SLS) or sodium taurocholate (NaTC), into PVP maintained that NMD supersaturation demonstrated different effects: SLS could only improve NMD supersaturation with concentration above its critical aggregation concentration (CAC) value while not with lower concentration. Nevertheless, NaTC could prolong NMD supersaturation independent of concentration, with lower concentration outperformed higher concentration. We attribute these observations to PVP-surfactant interactions and the formation of PVP/surfactant complexes. In summary, despite the lack of specific interactions in the nonaqueous state, NMD aqueous supersaturation in the presence of PVP was attained by hydrophobic interactions between the hydrophobic moieties of NMD and PVP. This hydrophobic interaction could be disrupted by surfactants, which interact with PVP competitively, thus hindering the capability of PVP to maintain NMD supersaturation. Therefore, caution is needed when evaluating such ASDs in vitro and in vivo when various surfactants are present either in the formulation or in the surrounding medium.

Asunto(s)

Sistemas de Liberación de Medicamentos/métodos , Excipientes/química , Nimodipina/química , Tensoactivos/química , Disponibilidad Biológica , Liberación de Fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética , Nimodipina/administración & dosificación , Nimodipina/farmacocinética , Polivinilos/química , Pirrolidinas/química , Dodecil Sulfato de Sodio/química , Solubilidad , Ácido Taurocólico/química

RESUMEN

Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 µg/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments.

Asunto(s)

Bloqueadores de los Canales de Calcio/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Nimodipina/administración & dosificación , Polietilenglicoles/administración & dosificación , Administración Oral , Animales , Ansiedad/sangre , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/sangre , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Cognición/efectos de los fármacos , Corticosterona/sangre , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos C57BL , Nanopartículas/química , Fármacos Neuroprotectores/sangre , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacocinética , Nimodipina/sangre , Nimodipina/química , Nimodipina/farmacocinética , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ratas Wistar , Estrés Psicológico/sangre , Estrés Psicológico/tratamiento farmacológico

RESUMEN

In this study, spherical shaped chiral mesoporous silica nanoparticles (CMS) was biomimetic synthesized using histidine derivatives (C16-L-histidine) as template via the sol-gel reaction and employed as poorly water-soluble drug nimodipine (NMP) carrier. Characteristics of CMS and its application as drug carrier were intensively investigated and compared with MCM41. Then NMP was respectively loaded into CMS and MCM41 with the drug: carrier weight ratio of 2:1. Structural features of NMP before and after drug loading were systemically characterized. The results demonstrated that hydrogen bonds were formed between NMP and carriers during the drug loading process. After drug loading, crystalline state of NMP effectively converted into modification L and amorphous state, and the first form turned out to be easily removed by washing. On the other hand, drug dissolution rate was significantly improved after drug loading, and the best result came from NMP-C3 sample. It was able to release 17.83% of drug within 60 min, which was 6.8-fold higher than the release amount of pure NMP. Undoubtedly, NMP-C3 presented the highest relative bioavailability (386.22%), and the best therapeutic effect. Meanwhile, CMS improved the brain distribution of NMP in vivo.

Asunto(s)

Materiales Biomiméticos , Biomimética , Bloqueadores de los Canales de Calcio/administración & dosificación , Portadores de Fármacos , Histidina/síntesis química , Nimodipina/administración & dosificación , Dióxido de Silicio/síntesis química , Tecnología Farmacéutica/métodos , Agua/química , Administración Oral , Animales , Disponibilidad Biológica , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Rastreo Diferencial de Calorimetría , Cristalografía por Rayos X , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Composición de Medicamentos , Liberación de Fármacos , Histidina/análogos & derivados , Enlace de Hidrógeno , Hipoxia Encefálica/inducido químicamente , Hipoxia Encefálica/prevención & control , Masculino , Ratones , Estructura Molecular , Nimodipina/química , Nimodipina/farmacocinética , Porosidad , Ratas Sprague-Dawley , Nitrito de Sodio , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Distribución Tisular